Citation or identification of any reference herein, or any section of this application shall not be construed as an admission that such reference is available as prior art to the present application. The disclosures of each of these publications and patents are hereby incorporated by reference in their entirety in this application, and shall be treated as if the entirety thereof forms a part of this application.
Microcins are a class of bacteriocin antibacterial products produced by bacteria with the ability to directly or indirectly kill or inhibit other bacterial species (Duquesne et al., 2007, Microcins, gene-encoded antibacterial peptides from enterobacteria, Natural Product Reports, 24: 708-734, Hen and Jack, Chapter 13 Microcins, in Kastin (ed.), 2006, Handbook of Biologically Active Peptides, Academic Press; Alouf and Popoff (eds.), 2006, Comprehensive Sourcebook of Bacterial Protein Toxins, Third Edition, Academic Press). Use of bacteriocins, including colicins and microcins, for the treatment of cancer has previously been suggested (WO 2001/014579; WO 2003/074554). However, the use of methionine analogue or microcin methionine synthesis inhibitors, methionine analogues, derivatives or isomers, or tRNA-methionine synthase inhibitors has not previously been suggested for the treatment of cancer.
Coronary heart disease is associated with elevated levels of homocysteine (hyperhomocysteinemia; Eikelboom et al., 1999, Homocysteine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med. 131:363-375). Homocysteine is a homologue of the amino acid cysteine containing an additional methylene (—CH2) group. It is synthesized from methionine by the removal of the methyl group, and can be reconverted to methionine by re-addition of the methyl group. Treatments for hyperhomocysteinemia include betaine, which enhances the reconversion of homocysteine to methionine. Suggested treatments have also included thetin for enhancing the conversion of homocysteine to methionine (U.S. Pat. No. 5,668,173). Methods for measuring methionine (WO 2005/070014), S-adenosyl-methionine (SAM; WO 2001/051651) cysteine (WO 2003/044220) and homocysteine levels have been described (U.S. Pat. No. 6,020,206; WO 2001/000853; WO 2004/023097) and are known to those skilled in the art. Treatments blocking conversion of methionine to homocysteine using bacterial microcins, methionine analogues, tRNA-methionine synthase inhibitors or methionine synthesis inhibitors have not been previously suggested.
Methionine analogues described by Bassiri and Rahimi-Larijani (WO/201001493) did not include microcins as methionine analogues or inhibitors of methionine metabolism. Bacterial species are known to be susceptible to agents such as bacteriocins including microcins. However, methionine analogue microcins have not been suggested to have broad antiinfective activity. The types of infectious diseases for which methionine analogue microcins are effective may generally include prions, viruses (e.g., hepatitis C), bacteria (e.g., Staphylococcus aureus, Pseudomonas aeruginosa), protozoans (e.g., Entamoeba histolytica, plasmodium falciparum), fungi (e.g., Candida albicans, Pneumocystis carnii) and helminthes (e.g., Ancylostoma duodenale, Schistosoma mansoni), (Mandell, Bennett and Dolin 2010, Principles and Practices of Infectious Diseases, 7th Edition, Elsevier Publishers, 4320 pages).